As a novel targeted therapy, ADC has gained fast development in recent years. So far there have been three ADC drugs (Mylotarg, Adcetris, and Kadeyla) approved by FDA, and more than 30 ADC drug candidates are in clinical trials worldwide.
An ADC drug is composed of three independent parts: an antibody or antibody-like ligand, high-potency cytotoxic drugs, and linkers that conjugate the drugs to the ligand. The mechanism of action (MOA) of an antibody-drug conjugate is described as follows. An antibody or antibody-like ligand targets specific cell surface protein receptors (antigens). Once binding to the antigens, the binding complex will internalize and thus deliver the linked drugs into the cell. The antibody or antibody-like ligand will be digested by enzymes, or the linkers will be cleaved, via either way the high-potency cytotoxic drugs could be released in an active form and kill the cells.
Cytotoxic drugs used in ADCs are required to be highly potent, normally 10-1000 folds higher than those first-line chemotherapy drugs in use. Currently used cytotoxic drugs mainly target cell microtubules or DNAs. Cytotoxic drugs targeting microtubules generally inhibit cell mitosis and thus lead to cell death, which include maytansinoids (EP 0425235; U.S. Pat. Nos. 5,208,020, 5,416,064; 7,276,497, 7,473,796, 7,851,432; US 2007/0269447, 2011/0158991; WO 2004/103272, 2012/061590) and auristatins (dolastatin 10 derivatives, U.S. Pat. Nos. 6,884,869, 7,498,298), etc. Cytotoxic drugs targeting DNAs generally kill the cells by DNA synthesis inhibition, minor-groove binding and alkylating, and DNA breaking, etc, which include doxorubicins (Bioconjugate Chem. 2002, 13, 855-869), calicheamicins (U.S. Pat. Nos. 5,606,040, 5,770,710), duocarmycins and CC-1065 (U.S. Pat. No. 7,129,261), and PBD dimers (WO 2005/040170), etc.
Around 70-80% of ADCs approved by FDA and in clinical trials adopts auristatins and maytansinoids as high-potency warheads. Maytansinoids are synthesized from ansamitocin (P-3), which is produced by fermentation, requiring high-production strains and optimized fermentation conditions. Auristatins can be produced by total synthesis and thus more convenient for scale production.
The representative auristatins are mono-methyl auristatin E (MMAE, U.S. Pat. No. 6,884,869) and mono-methyl auristatin F (MMAF, U.S. Pat. No. 7,498,298), both of which are pentapeptide derivatives of dolastatin 10, while the latter was isolated from the marine mollusk Dolabella auricularia and found to be highly potent cytotoxic agent. Besides widely used MMAE and MMAF mentioned above, other analogs of dolastatin 10 were also reported. WO 2006/132670 disclosed derivatives with N-terminal valine substituted by p-aminobenzoic acid. WO 2007/008603, WO 2007/008848, US 2013/0123456 and WO 2013/173393 disclosed a series of derivatives with C-terminal modification on phenylalanine. WO 2011/154359 and WO 2012/041805 disclosed derivatives based on structural modification on both N-terminal and C-terminal of MMAF.
Due to the high potency requirement for cytotoxic agents (for ADCs), both types and amounts of cytotoxic drug candidates are relatively few, which somehow limit the development of ADCs. Therefore, more potent cytotoxic agents are required by this area. Development of novel cytotoxic drugs based on current cytotoxic agent is of great importance and application prospect.